Coated medical device and method for manufacturing the same

ABSTRACT

The medical device of the invention comprises a surface comprising at least one outermost portion and a plurality of depressions. The depressions occupy at least about 80% of the surface area of the surface. The depressions contain a coating material that preferably comprises a biologically active material and/or polymer, and the outermost portion is substantially free of any coating material. The invention is also directed to a method for manufacturing a medical device. The method comprises applying a coating material to the surface of the medical device by using at least one roller.

FIELD OF THE INVENTION

This invention relates generally to medical devices having a coating.The medical device is capable of delivering a biologically activematerial to a desired location within the body of a patient. Moreparticularly, the invention is directed to medical devices having asurface comprising at least one outermost portion and a plurality ofdepressions. The depressions contain a coating material preferablycomprising a biologically active material, and the outermost portionsare substantially free of any coating material. The invention is alsodirected to a method and system for manufacturing a coated medicaldevice involving the use of roller(s).

BACKGROUND OF THE INVENTION

It has been proposed that a variety of medical conditions can be treatedby introducing an insertable or implantable medical device having acoating for release of a biologically active material. For example,various types of drug-coated stents have been proposed for localizeddelivery of drugs to a body lumen. See U.S. Pat. No. 6,099,562 to Dinget al.

However, the coatings for a medical device can exhibit problems ofcracking especially when the device is exposed to harsh conditions, suchas low temperatures and/or mechanical deformations. For example, aself-expanding stent must be contracted and loaded into a deliverysheath before delivering into a patient's body. To contract aself-expanding stent made of a shape-memory alloy, it must be chilled tobe thermally induced into the Martenstic phase, in which theshape-memory alloy can be plastically deformed. In practice, theself-expanding stent is chilled to about −80° to −100° C. and thenwarmed to about −60° to −20° C. when it is contracted. However, theprocessing temperature about −60° to −20° C. is usually the same as orlower than the glass transition temperatures of many polymers.Therefore, when chilled to these temperatures, a polymer coating on thestent is in a condition like glass and particularly vulnerable tostress-cracking when the device is processed.

The risk of cracking the coating is particularly high in certain partsof the coated stent, such as the apex regions of a zigzag strutconfiguration where the surface of the strut is greatly deformed bycontraction of the stent as shown in FIGS. 1, 1 a and 2. FIG. 1 shows aschematic view of a portion of a stent 10 having struts 11 in itsexpanded state. The apex regions of the zigzag strut configuration 12are magnified in FIG. 1 a. FIG. 2 shows a schematic view of the sameapex regions 12 when the stent is in its contracted state and the cracks13 in the coating that may occur at the apex regions. Cracks in thecoating are undesirable because they can cause the coating to flake orseparate from the coated surface of the device while the coated medicaldevice is inside the body of a patient. Such separated or loose piecesof coating can cause emboli. Hence, there is a need for a coated medicaldevice wherein a risk of cracks in the coating is reduced.

Furthermore, when a medical device such as a stent is delivered to theimplantation site, the coated surface of the medical device is oftencovered by a sheath to prevent the coating from being removed before themedical device is inserted and appropriately located inside the body.Also, if the coated surface of the medical device is self-expanding, asheath is used to contract the portion so that the device can beinserted, such as in the case of a self-expanding stent. However, thesheath is likely to contact the coating located on the outermost portionof the coated surface. The coating material at such outermost portionmay adhere to the sheath. When the sheath is withdrawn, the adheredcoating may be torn or removed from the coated device. Therefore, thereis a need for a coated medical device that avoids such undesired tearingof the coating.

Also, the conventional methods for coating medical devices requireencapsulating the device or coating entire surfaces of the device.However, in many medical devices, not all of the surfaces or theentirety of the surfaces of the medical device need to be coated. Forinstance, in medical devices having a tubular portion, such as avascular stent, the inner surface of the tubular portion does not haveto be coated with a coating containing a biologically active materialthat is used to treat only the body lumen wall that contacts the outersurface of the stent. This is because the inner surface of the stentdoes not come in contact with body-lumen wall and does not apply thebiologically active material to the body-lumen wall. When all thesurfaces of a medical device such as a stent, including surfaces thatare not directly in contact with the body tissue of a patient, arecoated with a composition comprising a biologically active material,more biologically active material is used than is needed. Thus, thepatient may receive unnecessary exposure to the material. Also,manufacturing costs for the medical device may be needlessly increasedby including unnecessary amounts of the biologically active material inthe medical device.

Moreover, if the medical device is an expandable stent, the coating onthe sides of the struts may adhere to each other when the stent isplaced in its contracted state. When the stent is expanded, the adheredcoating may be removed from the struts. In addition, if the medicaldevice is a balloon expandable stent, the coating on the inner surfaceof the stent has higher risk of damage because it directly contacts theballoon and is pressed by a balloon. Such damage is undesirable becausethe damaged coating may separate from the device while the device isinserted in a patient. Accordingly, there is a need for a method thatcan coat only the outer surface of a medical device or the surface thatdirectly contacts the body tissue to be treated.

SUMMARY OF THE INVENTION

The present invention is directed to a medical device comprising astructure. The structure has a thickness and a surface. The surface ofthe structure comprises at least one outermost portion and a pluralityof depressions. These depressions occupy at least about 80% of thesurface area of the surface. Also, at least one of the depressionscontain a coating material. Preferably, a majority of the depressionscontain coating material. The outermost portion of the surface issubstantially free of any coating material. This coating material cancontain a biologically active material and/or a polymer.

Furthermore, the present invention relates to a method for manufacturinga medical device. In this method, a medical device having a surface isobtained. The surface of the medical device comprises at least oneoutermost portion and a plurality of depressions. The depressions occupyat least about 80% of the surface area of the surface. A coatingmaterial is applied to the surface of the medical device in a mannersuch that the outermost portion of the surface is substantially free ofany coating material and the coating material is present in at least oneof the depressions. The outermost portion may be made substantially freeof the coating material by removing the coating material from theoutermost portion.

In addition, another embodiment of the invention involves a system and amethod for manufacturing a medical device having at least a tubularportion, wherein the tubular portion has a surface. In this system acoating material is applied on a surface of a first roller. The coatingmaterial is then transferred from the first roller surface to thesurface of the tubular structure. Also, if there is an excess amount ofthe coating material on the first roller surface, it can be removed,e.g., by a doctor blade, before the coating material is transferred tothe surface of the tubular portion. Additionally, the method can involvea second roller. The coating material on the first roller surface istransferred onto a surface of a second roller. Then, the coatingmaterial is transferred from the second roller surface to the outersurface of the tubular portion.

The present invention also pertains to a system for coating a medicaldevice having a tubular portion with an outer surface. The systemcomprises a coating material source containing a coating material. Thesystem also includes a roller having a surface, in which the roller issituated relative to the coating material source so that the coatingmaterial in the coating source can be transferred to the roller surface.Also, the roller is situated relative to the outer surface of thetubular portion so that the roller surface can transfer the coatingmaterial transferred to the roller surface onto the outer surface of thetubular portion. The system can further include a reservoir thatcontinuously supplies the coating material source with coating material.In addition, the surface of the roller can comprise a plurality ofgrooves.

In another embodiment, the system for coating a medical device comprisesa coating material source containing a coating material, a first rollerhaving a surface and a second roller having a surface. The first rolleris situated relative to the coating material source so that the coatingmaterial in the coating material source can be transferred to the firstroller surface. The first roller and second roller are situated relativeto each other so that the first roller can transfer the coating materialtransferred to the first roller surface to the second roller surface.The second roller is situated relative to the tubular portion so thatthe second roller can transfer the coating material transferred to thesecond roller surface to the outer surface of the tubular portion. Thesurface of the second roller can be rougher than the surface of thefirst roller. Preferably, the first roller contacts the surface of thesecond roller and the surface of the second roller contacts the outersurface of the tubular portion. Also the system can include a mechanismfor removing excess coating material from the surface of the firstroller. Furthermore, the system can include an energy source forconverting the coating material applied to the outer surface of thetubular portion into a coating.

In yet another embodiment, the system comprises a coating materialsource containing a coating material; a first roller having a surface; asecond roller having a surface; a third roller having a surface; and aflexible webbing material position around the second and third rollers.The first roller is situated relative to the coating material source sothat the coating material can be transferred to the first rollersurface. The first roller and webbing are situated relative to eachother so that the first roller can transfer the coating materialtransferred to the first roller surface to the webbing. Additionally,the webbing is situated relative to the tubular portion so that thewebbing can transfer the coating material transferred to the webbing tothe outer surface of the tubular portion. Preferably, the webbingcontacts the outer surface of the tubular portion.

The present invention is also directed to a system for coating a medicaldevice having a tubular portion with an outer surface in which thesystem comprises a roller having a surface and an applicator forapplying an adhesion protein to the roller surface. The roller issituated relative to the tubular portion so that the roller can transferthe adhesion protein to the outer surface. The outer surface is exposedto a cell suspension and the adhesion protein can be transferred to theouter surface as the outer surface is simultaneously exposed to the cellsuspension.

Moreover, the present invention is directed to a lithographic method forcoating a medical device having a tubular portion with an outer surface.The method comprises providing a layer of an unsolidified gel. Acrosslinking agent is applied onto the outer surface of the tubularportion. The crosslinking agent is transferred from the outer surface ofthe tubular portion to the gel layer by rolling the tubular portion overthe gel layer to form a crosslinked, planar replica of the outer surfaceonto the unsolidified gel to crosslink the unsolidified gel. An adhesivematerial is applied onto the outer surface of the tubular portion. Thetubular portion is rolled over the gel in the same manner as the firsttime the tubular portion was rolled over the gel so that the crosslinkedplanar replica is aligned with and attaches to the outer surface of thetubular portion.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically depicts a portion of a stent comprising struts inits expanded state. FIG. 1 a is a magnified view of the link-connectedapex regions of the stent struts depicted in FIG. 1.

FIG. 2 schematically depicts the same link-connected apex regions as inFIG. 1 when the stent is in its contracted state.

FIG. 3 depicts a cross-sectional view of a stent in which a surface ofthe stent struts are comprised of a plurality of outermost portions anda plurality of depressions.

FIG. 3 a depicts a magnified view of a cross-section of the struts ofthe stent depicted in FIG. 3.

FIG. 4 depicts a top view of a stent strut having a surface comprised ofoutermost portions and a plurality of depressions.

FIGS. 5A, 5B, 5C and 5D depict cross-sectional views of depressions inwhich the depressions have various cross-sectional configurations.

FIG. 6A is a schematic illustration of a pressure-rolling method formaking depressions on a surface of a medical device.

FIG. 6B depicts a magnified cross-sectional view of the surface of themedical device shown in FIG. 6A.

FIG. 7A is a schematic illustration of a method for forming outermostportions of the surface that extend over the depression in the surfaceof a medical device.

FIG. 7B depicts a magnified cross-sectional view of the surface of themedical device in FIG. 7A.

FIGS. 7C, 7D and 7E show depressions containing coating material.

FIGS. 8A, 8B and 8C are schematic illustrations of embodiments of acoating system having a roller.

FIGS. 9A, 9B, 9C, 9D and 9E are schematic illustrations of embodimentsof a coating system having two rollers.

FIG. 10 is a schematic illustration of a coating system comprisingrollers and a webbing.

FIG. 11 is a schematic illustration of another coating system comprisingrollers.

FIGS. 12A, 12B, 12C, 12D, 12E and 12F illustrate patterns of groovesthat may appear on the roller surfaces.

FIG. 13 illustrates a system for coating medical devices involving anadhesion protein and a cell suspension.

FIGS. 14A, 14B, 14C and 14D illustrate a lithographic coating method.

DETAILED DESCRIPTION OF THE INVENTION

1. Suitable Medical Devices

The medical devices of the present invention can be inserted and may beimplanted into the body of a patient. The medical devices suitable forthe present invention include, but are not limited to, stents, surgicalstaples, catheters, such as central venous catheters and arterialcatheters, guidewires, cannulas, cardiac pacemaker leads or lead tips,cardiac defibrillator leads or lead tips, implantable vascular accessports, blood storage bags, blood tubing, vascular or other grafts,intra-aortic balloon pumps, heart valves, cardiovascular sutures, totalartificial hearts and ventricular assist pumps, and extra-corporealdevices such as blood oxygenators, blood filters, hemodialysis units,hemoperfusion units and plasmapheresis units.

Medical devices of the present invention include those that have atubular or cylindrical-like portion. The tubular portion of the medicaldevice need not to be completely cylindrical. For instance, thecross-section of the tubular portion can be any shape, such asrectangle, a triangle, etc., not just a circle. Such devices include,without limitation, stents and grafts. A bifurcated stent is alsoincluded among the medical devices which can be fabricated by the methodof the present invention.

Medical devices which are particularly suitable for the presentinvention include any kind of stent for medical purposes which is knownto the skilled artisan. Suitable stents include, for example, vascularstents such as self-expanding stents and balloon expandable stents.Examples of self-expanding stents useful in the present invention areillustrated in U.S. Pat. Nos. 4,655,771 and 4,954,126 issued to Wallstenand U.S. Pat. No. 5,061,275 issued to Wallsten et al. Examples ofappropriate balloon-expandable stents are shown in U.S. Pat. No.5,449,373 issued to Pinchasik et al.

The medical devices suitable for the present invention may be fabricatedfrom metallic and/or polymeric materials. Metallic material is morepreferable. Suitable metallic materials include metals and alloys basedon titanium (such as nitinol, nickel titanium alloys, thermo-memoryalloy materials), stainless steel, tantalum, nickel-chrome, or certaincobalt alloys including cobalt-chromium-nickel alloys such as Elgiloy®and Phynox®. Metallic materials also include clad composite filaments,such as those disclosed in WO 94/16646. Suitable polymeric materialsinclude, without limitation, polyurethane and its copolymers, siliconeand its copolymers, ethylene vinyl-acetate, polyethylene terephtalate,thermoplastic elastomers, polyvinyl chloride, polyolefins, cellulosics,polyamides, polyesters, polysulfones, polytetrafluorethylenes,polycarbonates, acrylonitrile butadiene styrene copolymers, acrylics,polylactic acid, polyglycolic acid, polycaprolactone, polylacticacid-polyethylene oxide copolymers, cellulose, collagens, and chitins.

In embodiments of the present invention, the insertable or implantableportion of the medical device of the present invention has a thicknessand a surface that comprises at least one outermost portion and aplurality of depressions. The term “depression” refers to anindentation, receptacle or groove in the surface. The depression canhave any cross-sectional configuration or shape. The term “outermostportion of the surface” refers to the highest portion of the surface ofthe medical device or that portion of the device surface that is mostlikely to first contact body tissue upon insertion of the device. Thedepressions occupy at least about 80% of the surface area of the surfaceupon which the coating is disposed, preferably at least about 90% of thesurface area of the surface. Having the depressions occupy at leastabout 80% of the surface area allows the administration of high amountsof a drug or biologically active material. Also, by having thedepressions occupy at least about 80% of the surface area allows for thedelivery of a drug or biologically active material evenly over most ofthe surface area.

FIG. 3 shows a cross-sectional view of a stent 30 having struts 32. FIG.3 a is a magnified view of a cross-section of one of the struts 32. Thestrut has an inner surface 35, outer surface 31 and side surfaces 33.The outer surface 31 comprises outermost portions 36 and depressions 37.In the present invention it is preferred that the depressions have amaximum depth α i.e., deepest part, of about 4% to about 20% of themaximum thickness β of the strut 32 or structure of the medical device(see FIG. 3 a). More preferably, the maximum depth of the depressions isabout 6% to about 10%, of the maximum thickness of the strut orstructure 32 of the medical device.

FIG. 4 shows a top view of a portion of a stent strut 41 having asurface having outermost portions 43 and depressions 45. As shown inthis figure the plurality of depressions cover at least 80% of thesurface area of the surface of the strut 41. The depression can havewidths or diameters that are uniform or the depressions can have varyingwidths or diameters.

Furthermore, examples of suitable cross-sectional configurations orshapes of the depressions are shown in FIGS. 5A-5D. Such suitablecross-sectional shapes include, but are not limited to, a truncatedcircle 37 a, a triangle 37 b, a rectangle or square 37 c and a truncateddiamond 37 d. Preferably, the depression 37 in the surface of the strut32 should be separated by an outermost portion 36. Also, preferably, theaverage width or diameter of the depression is about 80 μm to about 180μm. The depression can all have the same cross-sectional shapes or theshape can vary from depression to depression.

The depressions can be situated in a regular pattern, such as in a row,on the surface of the medical device as shown FIGS. 5A-5D. But thedepressions can also be arranged in any way, either in a regular patternor in a irregular manner. Also, the depressions do not have to bedeposed evenly on the entire surface of the medical device. In oneembodiment, the density of the depressions that are disposed on thesurface of the medical device is greater in areas where cracking of thecoating is likely to occur, such as apex regions 12 as shown in FIG. 2.In another embodiment, the depressions are more densely deposed on thesurface in areas where a stronger release of the biologically activematerial is desired. In yet another embodiment, the depressions arelocalized in one or more areas on the surface, and other areas of thedevice do not comprise depressions.

The depressions in the device surface can be formed by chemical etching,photo-etching, high-velocity particle impact (“blast methods”),pressure-rolling or laser ablation. The blast methods include a methodwherein various high-velocity and hard particles are blasted to asurface of the medical device. The pressure-rolling method involvesimpressing a hard die onto a flat perform surface of the medical device.The die surface being etched or machined to possess a number of smallprojections. Under pressure these projections indent the preform surfacewith suitable depressions. For example, FIG. 6A is a schematicillustration of a pressure-rolling method for making depressions 66 on asurface of a medical device 68. A roller 62 having small projections 64on its outer surface is used as the hard die. The roller 62 is rotated,and the projections 64 of the roller 62 are impressed onto the surfaceof a tubular medical device 68 to create the depressions 66 on thesurface of a part of a medical device, e.g., a strut. FIG. 6B depicts amagnified cross-sectional view of the medical device surface 68 havingthe depressions 66.

In another embodiment, the depressions can be modified after they areformed. For example, as shown in FIG. 7A, a roller 72 having a hard andpolished outer surface 74 is rotated, and the surface 74 is pressedagainst the outermost portions of the surface of tubular medical device78. FIG. 7B depicts a magnified cross-sectional view of the medicaldevice surface 78 having deformed depressions 76. The outermost portions75 are pressed or deformed so that the outermost portions 75 extend overthe depressions 76. By doing so the width of an upper portion of thedepressions is made smaller than the width of a lower portion of thedepressions. Such configuration is desirable since it enhances theability of the depressions to retain coating material. By varying thepressure with which the roller is impressed onto the medical surface, adesired degree of the deformation can be achieved.

2. Coating

In the present invention, a coating composition or material, whichpreferably contains a biologically active material, can be applied byany method to a surface of a medical device to form a coating. Themethod should apply the coating material in a manner such that thecoating material is deposited in the depressions, and the outermostportions of the surface are substantially free of any coating material.More specifically, the outermost portions of the surface contain none ornegligible amounts of any coating material.

Examples of suitable methods for applying the coating material arespraying, dipping, rolling, electrostatic deposition and all modemchemical ways of immobilization of bio-molecules to surfaces. One of thesuitable methods of applying a coating material to the medical device isa rolling technique, which is explained in detail in section 3, infra.Also, in one embodiment of the present invention, more than one coatingmethod can be used to make a medical device.

Furthermore, before applying the coating material, the surface of themedical device is optionally subjected to a pre-treatment, such asroughening, oxidizing, sputtering, plasma-deposition or priming inembodiments where the surface to be coated does not comprisedepressions. Sputtering is a deposition of atoms on the surface byremoving the atom from the cathode by positive ion bombardment through agas discharge. Also, exposing the surface of the device to a primer is apossible method of pre-treatment.

A coated medical device surface in which the coating material iscontained in the depressions and in which the outermost portions of thedevice surface are substantially free of any coating material providesseveral advantages. First, this coating reduces the risk that thecoating will crack when the coated portion of the medical device issubjected to mechanical stress, such as when a stent is expanded andcontracted. In the coating of the present invention, coating material isnot present on the entire surface of the medical device that is coated.The coating material is present in the depressions of the surface butsubstantially absent from the outermost portions of the device surface.Hence, the coating formed on the device surface is discontinuous becausethe coating material contained in a depression is generally notconnected by coating material to the coating material contained inanother depression since these depressions are separated by an outermostportion that is substantially free of such coating material. When amechanical stress is applied to the coated device surface, thelikelihood that the stress is transmitted throughout the coating on thedevice surface is greatly reduced because of the discontinuous nature ofthe coating. Transmission of compressive, tensile or shear stressesthroughout the coating is blocked because the coating materials in thedepressions are isolated from each other. By preventing transmission ofthese stresses throughout the coating, cracking of the coating due tothese stresses is reduced. For example, the risk that the coating in theapex regions 12 of struts 11 of a self-expanding stent 10 will crack asshown in FIG. 2, even if the stent is contracted at a temperature lowerthan the glass transition temperature of the coating material, isreduced.

In addition, the possibility that the coating is inadvertently orundesirably removed or abraded from the coated device surface is greatlyreduced in the present invention. For example, when the medical deviceis a self-expanding stent, a sheath is usually placed over the stent tocontact the stent during delivery of the stent to the implantation site.The outermost portion of the coated surface generally comes in contactwith the sheath. If coating material is placed over the outermostportions, such coating material can adhere to the sheath. When thesheath is removed, the coating on the device surface can be undesirablytorn or removed from the surface. However, in the present invention,because the outermost portions of the device surface, which contact thesheath are substantially free of coating material, the chances that thecoating on the device surface will be damaged will be reduced. Since theoutermost portions are substantially free of coating material, therewill be no adhering of such coating material to the sheath and noundesired removal of coating when the sheath is removed. Thus, thecoating will not be damaged when the coated self-expanding stent isloaded in a delivery sheath and exposed to continuous radial pressureagainst the inner wall of the sheath, even if the stent is loaded in thesheath for long period.

One way to ensure that the coating material is applied to the surface ina manner such that the outermost portions are substantially free of anycoating material is to remove such coating material from those outermostportions. In one embodiment, the coating material is removed using adoctor blade. The doctor blade is for example a flexible blade thatscrapes the coating material from the outermost portion of the surfaceof the medical device. Furthermore, a small roller engaged inroller-contact with the surface of the device can be used to ensure thatthe coating material is applied to the surface so that the outermostportions are substantially free of coating material. When the smallroller and the surface of the medical device are rotated, excess coatingmaterial is squeezed off the outermost surface of the medical device.Preferably, the small roller has a rubber surface. Also, the smallroller can have a groove into which an O-ring can be placed. When thesmall roller is engaged in roller-contact with the surface of thedevice, the O-ring can function as a modified doctor blade or wipe stripto remove the coating material from the outermost portion of the devicesurface.

In one embodiment, the medical device has a tubular portion where theouter surface is to be coated. The doctor blade is put in contact withsurface of the tubular portion which has been coated by the coatingmaterial. This portion is then rotated and the doctor blade removescoating material from the outermost portions of the surface. To maintainan appropriate pressure of the doctor blade on the surface, the doctorblade may be spring-loaded against the surface of the medical device.After the removal, the outermost portions of the surface aresubstantially free of the coating material. The term “substantially freeof a coating material” means that only a very small residual amount ofcoating material remains on the outermost portions of the surface orthat the outermost portions are covered with no coating material. Afterthe coating material is applied to the device surface and is removedfrom the outermost portions, the solvent evaporates to leave a polymericcoating material in the depressions.

Also, as shown in FIG. 7C, it is preferable that the coating material 77contained in the depressions 76 be contained entirely within thedepression 76. As seen in this figure, the coating material 70 isconfined within the depression 76 and the outermost portions of thesurface 75 are substantially free of coating material. However, thecoating material 77 can also extend beyond or above the depression 76 asshown in FIG. 7D, as long as the outermost portions 75 of the surfaceremain substantially free of coating material.

The coating material present in the depressions may comprise more thanone layer. For example, the coating can comprise a first layer and asecond layer disposed over the first layer. FIG. 7E shows such anembodiment. The depression 76 contains a first layer of coating material77 a and a second layer of coating material 77 b, which is disposed overthe first layer 77 a. The layers may contain the same or differentbiologically active materials. Alternatively, the first layer and thesecond layer may contain the same biologically active material but havedifferent concentrations of this material. In another embodiment, eitherthe first layer or the second layer may be free of biologically activematerial.

Coating compositions suitable for applying coating materials to thedevices of the present invention preferably include a polymeric materialand/or a biologically active material dispersed or dissolved in asolvent suitable for the medical device, which are known to the skilledartisan. The solvents used to prepare coating compositions include oneswhich can dissolve the polymeric material into solution or suspend thepolymeric material and do not alter or adversely impact the therapeuticproperties of the biologically active material employed. For example,useful solvents for silicone include tetrahydrofuran (THF), chloroform,toluene, acetone, isooctane, 1,1,1-trichloroethane, dichloromethane, andmixture thereof.

The polymeric material should be a material that is biocompatible andavoids irritation to body tissue. Preferably the polymeric materialsused in the coating composition of the present invention are selectedfrom the following: polyurethanes, silicones (e.g., polysiloxanes andsubstituted polysiloxanes), and polyesters. Also preferable as apolymeric material are styrene-isobutylene copolymers. Other polymerswhich can be used include ones that can be dissolved and cured orpolymerized on the medical device or polymers having relatively lowmelting points that can be blended with biologically active materials.Additional suitable polymers include, thermoplastic elastomers ingeneral, polyolefins, polyisobutylene, ethylene-alphaolefin copolymers,acrylic polymers and copolymers, vinyl halide polymers and copolymerssuch as polyvinyl chloride, polyvinyl ethers such as polyvinyl methylether, polyvinylidene halides such as polyvinylidene fluoride andpolyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinylaromatics such as polystyrene, polyvinyl esters such as polyvinylacetate, copolymers of vinyl monomers, copolymers of vinyl monomers andolefins such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS (acrylonitrile-butadiene-styrene)resins, ethylene-vinyl acetate copolymers, polyamides such as Nylon 66and polycaprolactone, alkyd resins, polycarbonates, polyoxymethylenes,polyimides, polyethers, epoxy resins, rayon-triacetate, cellulose,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, collagens, chitins, polylactic acid,polyglycolic acid, polylactic acid-polyethylene oxide copolymers, EPDM(etylene-propylene-diene) rubbers, fluorosilicones, polyethylene glycol,polysaccharides, phospholipids, and combinations of the foregoing.

More preferably for medical devices which undergo mechanical challenges,e.g., expansion and contraction, the polymeric materials should beselected from elastomeric polymers such as silicones (e.g.,polysiloxanes and substituted polysiloxanes), polyurethanes,thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefinelastomers, and EPDM rubbers. Because of the elastic nature of thesepolymers, the coating composition is capable of undergoing deformationunder the yield point when the device is subjected to forces, stress ormechanical challenge.

The term “biologically active material” encompasses therapeutic agents,such as drugs, and also genetic materials and biological materials. Thegenetic materials mean DNA or RNA, including, without limitation,DNA/RNA encoding a useful protein intended to be inserted into a humanbody including viral vectors and non-viral vectors. Viral vectorsinclude adenoviruses, gutted adenoviruses, adeno-associated virus,retroviruses, alpha virus (Semliki Forest, Sindbis, etc.), lentiviruses,herpes simplex virus, ex vivo modified cells (e.g., stem cells,fibroblasts, myoblasts, satellite cells, pericytes, cardiomyocytes,sketetal myocytes, macrophage), replication competent viruses (e.g.,ONYX-015), and hybrid vectors. Non-viral vectors include artificialchromosomes and mini-chromosomes, plasmid DNA vectors (e.g., pCOR),cationic polymers (e.g., polyethyleneimine, polyethyleneimine (PEI))graft copolymers (e.g., polyether-PEI and polyethylene oxide-PEI),neutral polymers PVP, SP1017 (SUPRATEK), lipids or lipoplexes,nanoparticles and microparticles with and without targeting sequencessuch as the protein transduction domain (PTD). The biological materialsinclude cells, yeasts, bacteria, proteins, peptides, cytokines andhormones. Examples for peptides and proteins include growth factors(FGF, FGF-1, FGF-2, VEGF, Endotherial Mitogenic Growth Factors, andepidermal growth factors, transforming growth factor α and β, plateletderived endothelial growth factor, platelet derived growth factor, tumornecrosis factor α, hepatocyte growth factor and insulin like growthfactor), transcription factors, proteinkinases, CD inhibitors, thymidinekinase, and bone morphogenic proteins (BMP's), such as BMP-2, BMP-3,BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8. BMP-9, BMP-10, BMP-11,BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferred BMP'sare BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7. These dimeric proteins canbe provided as homodimers, heterodimers, or combinations thereof, aloneor together with other molecules. Cells can be of human origin(autologous or allogeneic) or from an animal source (xenogeneic),genetically engineered, if desired, to deliver proteins of interest atthe transplant site. The delivery media can be formulated as needed tomaintain cell function and viability. Cells include whole bone marrow,bone marrow derived mono-nuclear cells, progenitor cells (e.g.,endothelial progentitor cells) stem cells (e.g., mesenchymal,hematopoietic, neuronal), pluripotent stem cells, fibroblasts,macrophage, and satellite cells.

Biologically active material also includes non-genetic therapeuticagents, such as:

-   -   anti-thrombogenic agents such as heparin, heparin derivatives,        urokinase, and PPack (dextrophenylalanine proline arginine        chloromethylketone);    -   anti-proliferative agents such as enoxaprin, angiopeptin, or        monoclonal antibodies capable of blocking smooth muscle cell        proliferation, hirudin, and acetylsalicylic acid, amlodipine and        doxazosin;    -   anti-inflammatory agents such as glucocorticoids, betamethasone,        dexamethasone, prednisolone, corticosterone, budesonide,        estrogen, sulfasalazine, and mesalamine;    -   antineoplastic/antiproliferative/anti-miotic agents such as        paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,        epothilones, methotrexate, azathioprine, adriamycin and        mutamycin; endostatin, angiostatin and thymidine kinase        inhibitors, taxol and its analogs or derivatives and cladribine;    -   anesthetic agents such as lidocaine, bupivacaine, and        ropivacaine;    -   anti-coagulants such as D-Phe-Pro-Arg chloromethyl keton, an RGD        peptide-containing compound, heparin, antithrombin compounds,        platelet receptor antagonists, anti-thrombin antibodies,        anti-platelet receptor antibodies, aspirin (aspirin is also        classified as an analgesic, antipyretic and anti-inflammatory        drug), dipyridamole, protamine, hirudin, prostaglandin        inhibitors, platelet inhibitors and tick antiplatelet peptides;    -   vascular cell growth promoters such as growth factors, Vascular        Endothelial Growth Factors (FEGF, all types including VEGF-2),        growth factor receptors, transcriptional activators, and        translational promoters;    -   vascular cell growth inhibitors such as antiproliferative        agents, growth factor inhibitors, growth factor receptor        antagonists, transcriptional repressors, translational        repressors, replication inhibitors, inhibitory antibodies,        antibodies directed against growth factors, bifunctional        molecules consisting of a growth factor and a cytotoxin,        bifunctional molecules consisting of an antibody and a        cytotoxin;    -   cholesterol-lowering agents; vasodilating agents; and agents        which interfere with endogenous vasoactive mechanisms;    -   anti-oxidants, such as probucol;    -   antibiotic agents, such as penicillin, cefoxitin, oxacillin,        tobranycin, and rapamycin,    -   angiogenic substances, such as acidic and basic fibrobrast        growth factors, estrogen including estradiol (E2), estriol (E3)        and 17-Beta Estradiol; and    -   drugs for heart failure, such as digoxin, beta-blockers,        angiotensin-converting enzyme (ACE) inhibitors including        captopril and enalopril.

3. Coating System Comprising Roller(s)

The present invention also comprises a method and a system formanufacturing a medical device by applying a coating material to thesurface of a tubular portion of the device using at least one roller. Inthe system, a first roller rotates through a coating material source towet a surface of the first roller with the coating material. A doctorblade contacts the surface of the first roller to remove any excessamount of the coating material from the roller surface. Afterward, thecoating material on the first roller surface is transferred to thesurface of the tubular portion of the medical device.

The doctor blade is a flexible blade and may have a curved edge. It isused to make uniform the coating material on the surface of the firstroller and also to control the thickness of the coating material on thesurface of the roller by removing any excess amount of the coatingmaterial. To maintain an appropriate pressure of the doctor bladeagainst the roller surface, the doctor blade may be spring-loaded. Also,the doctor blade can be used in conjunction with another roller, such asa metering roller to control the amount of coating material applied tothe roller. Moreover, instead of or in addition to the doctor blade, anair source or air knife may be used to control the thickness or amountof coating material applied to the roller. For example, the highpressure air of the air knife or air source removes undesired amounts ofthe coating material from the roller.

The coating material source may be connected to a main reservoir, whichcontains the coating material. For instance, in the case of cell therapycoatings, the coating material source may be connected to a reservoirthat is a fermentor for cells or cell culture reservoir, where cells aregrown and/or transduced with a particular gene therapy. The coatingmaterial can circulate between the reservoir and the coating materialsource. A valve system can be used to control flow between the coatingmaterial source and the cell culture reservoir. Sensor systems based onoptical density or fluorescence spectroscopy to assess particularprotein products generated by the cells can be used to trigger thevalve.

Furthermore, the main reservoir can be thermally jacketed to control thetemperature. By controlling the temperature, temperature sensitivehydrogels (i.e., poloxamers which are soluble at low temperatures andgel at elevated temperatures, can be coated onto the device. In the caseof cell therapy coatings, temperature control can be used to preservecell viability and/or trigger cell processes (i.e., induce heat shockproteins).

In one embodiment, the outer surface of the tubular portion of themedical device contacts the surface of the rotating first roller. Thetubular portion of the medical device is situated parallel to the firstroller and may rotate in a direction same as or opposite to the rotationof the first roller. Preferably, a tubular portion of the medical deviceto be coated is mounted on a mandrel or a tube which can be thermallyjacketed. When the portion of the medical device is expandable, such asin a self-expanding stent or a balloon expandable stent, the diameter ofthe mandrel or tube may be greater, preferably slightly greater, thanthe diameter of the tubular portion in its normally expanded state.

FIGS. 8A and 8B schematically depict a system of the present invention.A first roller 81 is situated relative to the coating material source sothat coating material can be transferred onto the roller surface.Preferably, the roller surface is in contact with the coating materialin the coating material source. The roller 81 rotates and the coatingmaterial 85 maintained in the coating material source 84 or 84′ istransferred to the surface of the first roller 86. In FIG. 8A, thecoating material source is contained in a box-like container, while inFIG. 8B, the coating material source is contained in a roundedcontainer. The doctor blade 83, which is flexible and preferably havinga curved edge, contacts the surface of the first roller 86 to ensurethat the coating material is uniformly placed on the roller surface 86and to remove any excess amount of the coating material 85 from theroller surface 86. The doctor blade can have a beveled or square edge.The tubular portion of the medical device 80 is situated relative to thefirst roller so that the first roller can transfer the coating materialto the outer surface of the tubular portion. The medical device canrotate reversely relative to the first roller 81. The device's outersurface should be close to, but not in actual contact with, the roller.It should however be in sufficiently close proximity to be in rollingcontact with the thin film of fluid coating material on the roller.

In another embodiment, a number of systems, each comprising roller(s)and coating material source(s) can be arranged in serial fashion. Themandrel, upon which the medical device is mounted, moves across eachsystem, allowing the outer surface of the device to be coated by thevarious types of coating materials of each system. In this way,different layers of coating material can be applied to the devicesurface. The layers can contain the same or different compositions.

In addition as shown in FIG. 8C, the system can also include an energysource 87 for facilitating the formation of a coating on the surface ofa medical device surface 80. The energy source 87 emits energy 88 suchas heat to help cure the coating material 85 applied to the devicesurface 80 or removal of solvents from the coating material applied tothe device. Preferably, only a small part of the device surface isexposed to the energy source at a given time. By limiting the area ofthe device surface that is exposed to the energy source, such as aheater, the environmental temperature of the area surrounding the systemcan remain low. Suitable energy sources include heaters, ultravioletlight and vacuum dryers, heating lamps, bone-dry air blowers, preheatedgases such as air or nitrogen, as well as ceramic fibre, multi-cell,strip, cast-in, fan, cable or cartridge type heaters. When anultraviolet source is used prepolymers or polymers that may be presentin the coating materials can be crosslinked or polymerized.

In other embodiments, the system uses more than one roller. For example,a second roller is used in addition to the first roller. After thecoating material on the surface of the first roller is made uniform bythe doctor blade, the coating material on the first roller surface istransferred to the surface of the second roller. The second roller canbe situated parallel to the first roller and may rotate in a directionsame as or opposite to the rotation of the first roller. In oneembodiment, another doctor blade may be used for controlling theuniformity and thickness of the coating material applied to the surfaceof the second roller. Afterward, the second roller transfers the coatingmaterial to the outer surface of the medical device. In otherembodiments, the distance between the rollers can be used to control thethickness of the coating material applied to the surface of the device.In this way, one of the rollers can function as a metering roller.

Examples of the systems having two rollers of the present invention areschematically depicted in FIGS. 9A and 9B. In these systems, the firstroller 91 is situated relative to the coating material source so thatthe coating material can be transferred onto the surface of the firstroller. Preferably, the first roller 91 rotates in contact with thecoating material 95 in the coating material source 94 or 94′, and thesurface of the first roller 91 is coated with the coating material 95. Adoctor blade 93 contacts the coated surface of the first roller 96 andmakes the coating material 95 on the roller surface uniform and alsoremoves any excess amount of the coating material 95 from the surface. Asecond roller 92 is situated relative to the first roller 91 so that thecoating material on the first roller's surface 96 can be transferred tothe surface of the second roller 97. Preferably, the second roller 92rotates in contact with the coated surface of the first roller 96. Thesecond roller 92 can rotate in the same or opposite direction as thefirst roller 91. The second roller 92 is situated relative to thetubular portion of the medical device so that the coating on the secondroller's surface 97 can be transferred to the outer surface of thetubular portion 90. Preferably, the outer surface of the tubular portionof the medical device 90 rotates reversely in contact with the surface97 of the rotating second roller 92, and the coating material on thesurface of the second roller 97 is transferred to the outer surface ofthe tubular portion 90. Inclusion of a second roller 92 enhances theuniformity of the coating material that is applied to the outer surfaceof the tubular portion 90.

Moreover, the rollers can be placed in various arrangements relative toeach other. For example, the rollers can be placed at an angle to eachother in FIGS. 9A and 9B. Additionally, the rollers may be placed on topof one another as in FIG. 9C or next to each other as in FIG. 9D.

In another embodiment, one of the rollers may be angled with respect tothe other roller as shown in FIG. 9E, and the medical device is situatedbetween the rollers. The rollers can turn in the same direction or inopposite directions. The angled roller 92 is used to move the coateddevice off the rollers. Furthermore, the surface of one of the rollerscan be rougher than the surface of the others to cause the stent torotate. Additionally, three or more rollers can be used in the systemand method of the present invention.

Also, a flexible webbing can be included in the system. In particular, aflexible webbing can be tightly extended between two rollers. Thewebbing can be used to transfer or apply the coating material onto themedical device surface. The use of a flexible webbing to apply thecoating material can reduce the chance of damage to the device, whichmay result from the pressure applied directly to the device surface by amore rigid roller. In certain applications, it may be desirable to pressthe device into the webbing to force the transfer of the coatingmaterial onto the device surface.

For example, FIG. 10 shows a system of four rollers and a webbing. Afirst roller 91 having a surface 96 contacts the coating material 95 incoating material source 94. Coating material on the first roller surface96 is transferred or applied to a flexible webbing 112 by rotating thefirst roller 91. The webbing is tightly extended between a second roller104 having a surface 106 and a third roller 108 having a surface 110.The flexible webbing can be made from various materials, including,without limitation, isobutylene, polyurethane or polyurethane rubbers,teflon, textured plastics, nitrite rubbers, and other types of rubbers.Suitable materials for the webbing are selected on the basis of flexureresistance and chemical compatibility with coating materials. Forinstance, thin, flexible stainless steel belting would also be suitable,and when used with a smooth and corrosion-resistant surface, should alsogive long, trouble-free performance. A rotating fourth roller 100 havinga surface 102 functions as a metering roller to control the thickness oramount of coating material that is applied to the webbing 112. A doctorblade 93 can also be used to control the amount and thickness of thecoating material applied to the webbing 112. The coating material on thewebbing 112 is applied to the surface of the device 90 as the rollersrotate.

Moreover, in yet another embodiment, a container is not used as part ofthe coating material source. Instead of placing the coating material ina container, the coating material is measured or metered into a regionbetween two rollers. The space or gap between the rollers controls theamount or thickness of the coating material that may be applied onto anapplicator roller, which is used to apply the coating material onto thedevice surface.

FIG. 11 shows an example of this embodiment. An amount of coatingmaterial 120 is placed between an applicator roller 122 having a surface124 and a metering roller 126 having a surface 128. A gap or space 132is located between the applicator roller 122 and metering roller 126. Amedical device 130 is situated relative to the applicator roller 122 sothat the coating material on the applicator roller 122 can betransferred or applied to the surface 131 of the tubular portion of themedical device 130. In this example, the device 130 is placed below theapplicator roller 122. However, the device 130 can be placed in anydesired position relative to the applicator roller 122. When the device130 is placed below the applicator roller 122, gravity assists in thetransfer of coating material from the applicator roller 122 to thesurface of the device 130.

One skilled in the art can determine an appropriate viscosity of thecoating material used for the method of the present invention.Generally, the viscosity of the coating material is slightly greaterthan that of the coating material used for a spray coating method. Thethickness of the coating material transferred to the device surface canbe affected by the viscosity as well as other characteristics of thecoating material.

Also, appropriate diameters of the rollers can be determined byartisans. The diameter of the first roller may be different from that ofthe second or other rollers. Preferably, the diameter is from about 100%to about 500% of the diameter of the tubular portion of the device to becoated. The rollers or their surface may be made of a relatively rigidor non-deformable material such as steel or a deformable material suchas rubber. One of skill in the art is aware of the appropriate rollermaterials that can be used in a given application.

Furthermore, the surface of the rollers may have a grooved pattern as ingravure rollers. Such rollers can be used to meter the amount of coatingmaterial that is applied to the applicator roller that applies thecoating material to the device surface. By selecting the pattern andsize of grooves in the roller surface for a particular application andcoating material, the desired amount or coverage can be applied to thedevice surface. FIGS. 12A, 12C and 12E show examples of grooved patternsthat can be used. FIG. 12A shows a pyramidal pattern. FIG. 12B shows across-section of the pattern of FIG. 12A along line A-A. FIG. 12C showsa truncated pyramidal pattern and FIG. 12D is a cross-section of thispattern along line B-B. Similarly, FIG. 12E shows a pattern, comprisingmultiple grooves with an obtuse angle and FIG. 12F shows itscross-section having shallow V-shapes along line C-C.

By using the method and system of the present invention, it is possibleto obtain a medical device having a tubular portion wherein the outersurface of the tubular portion has a coating but the inner surface doesnot have the coating. Also, the method and system involving rollers canbe used to apply coating material to a surface comprising a plurality ofdepressions as discussed above. Such method and system can be used toapply the coating material so that the coating material is contained inthe depressions but the outermost portion of the surface issubstantially free of the coating material. The coating for releasing abiologically active material can be applied only to the outer surfacewhich is directly exposed to body tissue of the patient. Also, anothercoating material can be applied on the outer surface of the tubularportion of the medical device by repeating the same method to obtain amultilayer coating on the outer surface of the tubular portion.

When more than two coating layers are to be applied on the tubularportion, the method of the present invention can be repeated. After thefirst coating layer, or underlayer which was applied by the method ofthe present invention, is dried, then the second coating layer or toplayer is applied on the under layer as explained above. Alternatively,another coating method can be used in combination with the coatingmethod of the present invention. Such combination of coating methods arepreferable when the first and second coating compositions are different.For instance, the first composition is applied to the outer surfacetubular portion of the medical device using the method of the presentinvention, and the second coating composition is applied to the innersurface using another method, such as a spraying coating. Also, anothermethod can be used first. For example, a drug coating is immobilized onthe surface, then another coating composition can be applied using themethod of the present invention.

In yet another embodiment, an adhesion protein (e.g., fibronectin) canbe applied to a device surface by using a roller. The device surfacecontaining such an adhesion protein can be exposed to a cell suspension.The adhesion protein enhances the coating of the cell suspension ontothe device surface.

FIG. 13 provides an example of such an embodiment. In this system, anadhesion protein applicator 150 applies an adhesion protein 152 to aroller 154 having a surface 156. The roller is situated relative to themedical device so that the adhesion protein applied to the roller 154can be transferred to the surface 160 of the medical device 158. As theroller 154 rotates, it transfers the adhesion protein 152 that isapplied to the roller surface 156 to the outer surface 160 of a medicaldevice 158, such as a stent. The medical device can be mounted on amandrel (not shown). Furthermore the outer surface of the medical deviceis exposed to a cell suspension 162 containing for example cells andextracellular matrix materials such as collagen, elastin, proteoglycansor fibronectin. Suitable cells are not limited to particular types. Forexample, cells that can be used with the invention include, withoutlimitation, fibroblasts, endothelial progenitor cells, endothelialcells, and mysenchymal stem cells. The use of this system results in amulti-laminate of cells and matrix on the stent. Also, the transfer ofthe adhesion protein from the roller to the outer surface of the devicemay but need not occur simultaneously with the exposure of the outersurface to the cell suspension.

In yet another embodiment, a medical device can be coated by using alithographic mechanism. This embodiment is depicted in FIGS. 14A, 14B,14C and 14D. A layer of an unsolidified gel 170 is formed as shown inFIG. 14A. The unsolidified gel 170 can contain biologically activematerials such as those discussed above. A medical device 172 whoseouter surface 174 is coated with a crosslinking agent 176 is rolled overthe unsolidified gel 170 as shown in FIG. 14B. Examples of suitablecross-linking agents include, without limitation, carbodimide,bifunctional aldehydes, calcium chloride, and sulfur. One of skill inthe art would be aware of the suitable cross-linking agents that can beused with the unsolidified gel. The device can have openings in theouter surface, such as a stent whose outer surface comprises a pluralityof struts.

By rolling the crosslinking agent-coated medical device 172 over theunsolidified gel 170, the gel becomes crosslinked only at the areas 178that contact the rolled device as shown in FIG. 14C. The openings in theouter surface of the device do not include crosslinking agents. Theseportions of the gel that are exposed to the openings 180 are notcrosslinked. The crosslinked portions 178 of the gel 170 form a planarreplica 182 of the outer surface of the rolled medical device. Thisplanar replica 178 is then transferred onto the outer surface 174 of themedical device 172 by coating the outer surface 174 with an adhesive. Asshown in FIG. 14D, the device 172 with the adhesive-coated outer surface174 is rolled back over the gel 170 in the same manner that the devicewas rolled over the gel 170 the first time (see FIG. 14B). This way theouter surface 174 of the medical device 172 will align with the planarreplica 178. The adhesive allows a crosslinked layer of gel 184 to forma coating 186 on the outer surface of the medical device 174. Since thecrosslinking agents can diffuse a significant distance into gels, athick coating 186 can result on the outer surface 174.

The description contained herein is for purposes of illustration and notfor purposes of limitation. Changes and modifications may be made to theembodiments of the description and still be within the scope of theinvention. Furthermore, obvious changes, modifications or variationswill occur to those skilled in the art. Also, all references cited aboveare incorporated herein, in their entirety, for all purposes related tothis disclosure.

1. A system for coating a stent having a tubular portion with an outersurface, wherein the system comprises: a coating material sourcecontaining a coating material comprising a solvent and a biologicallyactive material; a first roller having a surface; a doctor blade inproximity to the first roller surface positioned to remove excesscoating material from the first roller surface; and a second rollerhaving a surface, wherein: the first roller is situated relative to thecoating material source so that the coating material in the coatingmaterial source is transferred to the first roller surface; the firstroller and second roller are situated relative to each other so that thefirst roller transfers the coating material transferred to the firstroller surface to the second roller surface, and the second roller issituated relative to the tubular portion so that the second rollertransfers the coating material transferred to the second roller surfaceto the outer surface of the tubular portion.
 2. The system of claim 1,which further comprises a reservoir that continuously supplies thecoating material source with coating material.
 3. The system of claim 2,wherein the reservoir is a fermentor containing cells.
 4. The system ofclaim 2, wherein the coating material is circulated between thereservoir and the coating material source.
 5. The system of claim 1wherein the surface of the second roller comprises a plurality ofgrooves.
 6. The system of claim 1, wherein the surface of the secondroller is rougher than the surface of the first roller.
 7. The system ofclaim 1, wherein the surface of the first roller contacts the surface ofthe second roller and the surface of the second roller contacts theouter surface of the tubular portion.
 8. The system of claim 1, furthercomprising a supplemental mechanism for removing excess coating materialfrom the surface of the first roller.
 9. The system of claim 8, whereinthe supplemental mechanism is at least one of a metering roller or anair knife.
 10. The system of claim 1, further comprising an energysource for converting the coating material applied to the outer surfaceof the tubular portion into a coating.
 11. The system of claim 10,wherein the energy source is a heater.
 12. The system of claim 10,wherein the energy source is an ultraviolet source.
 13. The system ofclaim 1, wherein the biologically active material comprises a geneticmaterial.
 14. The system of claim 1, wherein the biologically activematerial comprises an antibiotic or an antiproliferative agent.
 15. Thesystem of claim 1, wherein said first roller surface comprises an outersurface.
 16. The system of claim 1, wherein a distance between the firstroller and the second roller is adjustable to control the thickness ofthe coating material.